Genetic Factor Extends Survival in People with ALS

Researchers funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) have identified a gene that affects how long people survive with the fatal neurological disease amyotrophic lateral sclerosis (ALS). The finding could lead to much needed drugs to slow the course of the disease.

ALS destroys the muscle-controlling nerve cells known as motor neurons. For some people, the disease begins with limb weakness; for others, it begins with difficulty swallowing and chewing. The disease worsens rapidly, usually leading to respiratory failure within 3-5 years of diagnosis.

ALS is genetic in about 10 percent of cases, but most cases are sporadic, meaning there is no known cause. In sporadic ALS, researchers suspect that a combination of genetic and environmental factors influence the risk of the disease and its severity. However, identifying those factors has been a challenge.

“In some respects, finding any gene associated with sporadic ALS is a surprise. This is not a common disease, which makes patient DNA samples difficult to obtain,” says John Landers, Ph.D., the first author of the new study and a professor of neurology at the University of Massachusetts Medical School (UMMS) in Worcester.

The study brought together nearly 20 research labs from 8 countries, allowing the investigators to pool their access to DNA samples and other resources. The senior investigators were Robert Brown, M.D., D. Phil., chair and professor of neurology at UMMS, and Ammar Al-Chalabi, Ph.D., a professor of neurology and complex disease genetics at King’s College London. At the time of the study, Drs. Landers and Brown held positions at Massachusetts General Hospital in Boston.

The study appears in the Proceedings of the National Academy of Sciences*, and is the latest in a series of genome-wide association (GWA) studies on ALS. In a GWA study, researchers scan the genome – the entire set of human DNA – in people affected by a disease and unaffected individuals, looking for genetic differences connected to the disease. Previous GWA studies have reported several genes that appear to affect the risk of ALS, but those findings have proven notoriously difficult to replicate.

In their GWA study, Dr. Landers and his colleagues scanned the genomes of about 1800 individuals with sporadic ALS and 2250 unaffected individuals from the U.S. and Europe. They did not find any genes that affect ALS risk, and could not confirm the risk genes that were reported in previous GWA studies.

Within the ALS group, they searched for genes related to age of onset, site of onset within the body, and survival data (available for about 1000 cases). They found that variations in a single gene called KIFAP3 were associated with variations in length of survival. The gene encodes a protein with a known function in motor neurons.

Having the most favorable variations of the KIFAP3 gene increased survival by 14 months on average. By comparison, riluzole, the only drug approved for treating ALS in the U.S., increases survival by about 2-3 months on average.

By analyzing blood cells and brain samples derived from people with sporadic ALS, the researchers also found that the survival-enhancing variants of KIFAP3 were associated with lower levels of gene activity and lower levels of KIFAP3 protein. So, high levels of KIFAP3 may contribute to faster disease progression.

Efforts to develop a drug therapy aimed at suppressing KIFAP3 are “at the beginning stages,” according to Dr. Landers. “We are thinking about the best way to target this gene and the best way to begin screening possible therapeutic compounds,” he says.

The researchers’ findings also shed some light on the biology of ALS. The KIFAP3 gene encodes a protein found in motor axons, the long tendrils that extend from motor neurons and connect to the body’s muscles. Complex machinery at the muscle end of the axon controls the release of chemicals that in turn control muscle contraction. KIFAP3 helps transport all the parts of that machinery to the right place. Consistent with the findings of Dr. Landers and his colleagues, previous studies have shown that heightened activity of the KIFAP3 gene is an early indicator of disease in a mouse model of ALS.

“The identification of the KIFAP3 gene as a survival factor in sporadic ALS adds to the evidence that defects in axonal transport play a role in the disease,” says Dr. Landers. It is not clear why high levels of KIFAP3 activity would be harmful to motor neurons.

The DNA samples used in the study were provided by the NINDS Human Genetics Resource Center and by repositories at King’s College London, Massachusetts General Hospital, and academic medical centers in Atlanta, the Netherlands and France.